Cancer chemotherapy has developed into an effective modality for cancer management. The concept of combination chemotherapy has played an important role in this remarkable progress. New drugs, analog development of existing anti-cancer drugs to minimize side effects, better use of current drugs, immunotherapy and combined modality therapy are the major concerns for the future progress in chemotherapy. In this application we propose to investigate the better use of two widely used drugs, Bleomycin and Adriamycin. A likely mechanism of cytotoxicity of these two agents is their ability to damage DNA. Biochemical evidence indicates that superoxide radical and Fe ions can enhance the Bleomycin effect on DNA, but that Cu ions can inhibit this process. Besides the direct effect of Adriamycin on DNA, it is known that Adriamycin interacts with membrane structures and as a result generates the superoxide radical (which itself is toxic) and promotes the cellular superoxide radical generating system which in turn can damage the cell or potentiate the effect of Bleomycin. A clinically used copper chelator, diethyldithiocarbamate (DDC), will be used as a model for a non-antitumor agent to promote the cytotoxicity of Bleomycin. The expected benefits of DDC are two-fold: (1) DDC can enhance the Bleomycin effect by lowering the copper concentration in serum which otherwise could rapidly become bound to Bleomycin and (2) DDC is an effective inhibitor for superoxide dismutase (SOD) which is an enzyme responsible for removing excess cellular superoxide radical. Hence, exposure of cells to DDC should result in an intracellular build-up of superoxide radical. We propose to study the cytotoxic effect of these mechanisms in cell culture and mouse tumor (B-16 melanoma) systems. We believe our study may provide the basis for redesigning treatment protocols based on the biochemical interactions of these drugs, and this principle may not be limited solely to Adriamycin and Bleomycin.